The Division of Perinatal Medicine, Department of Pediatrics, University of Alabama at Birmingham has the patients, professional personnel, and resources to more than meet the minimum and desirable requirements to participate, with NICHD and other major research centers, in a cooperative network of NICUs in order to develop priorities and to plan, implement and analyze a series of multicenter, randomized clinical trials designed to solve major unresolved dilemmas in current neonatal care practices. We also provide evidence of past and present excellence and experience in the planning and performance of clinical trials in newborn patients. We propose the first randomized, controlled trial of therapies in persistent pulmonary hypertension of the newborn (PPHN). At least 5,000 infants have PPHN and at least 1,500 of these die yearly in the U.S. Two therapies, tolazoline infusion and mechanical hyperventilation, have evolved without rigorous proof of efficacy for either. We propose 3 hypotheses: (1) tolazoline is more effective than placebo in raising distal aortic oxygen tension; (2) hyperventilation raises distal aortic oxygen tension in a higher percentage of infants with PPHN than does tolazoline; (3) hyperventilation maintains elevated distal aortic oxygen tension longer than does tolazoline. A multicentered trial is needed because PPHN is too rare to allow timely testing of the hypotheses within one center. Once PPHN is diagnosed, subjects will be randomized to receive either tolazoline or hyperventilation. Tolazoline and placebo will be given in a double blind crossover fashion at 15-minute intervals, and distal aortic oxygenation changes observed in order to test Hypothesis 1. Distal aortic oxygenation changes will also be used to test Hypothesis 2. Responders to a treatment will be maintained on that treatment until it fails or the infant recovers. We propose use of sequential methods to test hypothesis 1 and 2 and survival curve analysis to test Hypothesis 3. Multiple confounding factors complicate the design and execution of a study such as this. Performance of a properly designed study of therapy in PPHN will provide a scientific basis for future studies and improve the outlook for thousands of infants every year.